ABSTRACT Kaposi's sarcoma (KS) remains a highly prevalent malignancy in sub-Saharan Africa. Anti-retroviral therapy (ART) and associated immune reconstitution has been correlated with a dramatic decline in the prevalence of KS in the U.S. HIV-infected population, but the impact of ART on KS in sub-Saharan Africa is less clear. In Zambia, even with the scale up of ART, KS remains the second most common cancer among adult men. For women, it is the third most common. Early identification of KS and a pipeline to definitive diagnosis and appropriate treatments that are well-tolerated and minimize side-effects is an essential strategy that can be implemented in Zambia and will improve outcomes for KS patients. The overall goals of this application are to implement a strategy in Zambia to identify and diagnose KS early and couple diagnosis to prospective investigations of the underlying cause(s) of ART treatment successes and failures. The project team hypothesizes that factors such as HIV and KSHV viral load, genetics, and soluble proteins, or immunological parameters that preexist the administration of ART to KS patients impact the outcome of early KS therapy with ART alone. The identification of these risk factors can serve as prognostic markers for directing KS treatment decisions (whom to treat with ART alone, and whom with ART/chemo), and will enhance understanding of early KS disease pathogenesis. These activities will result in improved early identification and definitive diagnosis of a major AIDS-associated malignancy. These improvements, coupled with the risk factor and prognostic biomarker identification, will, in turn, improve the prognosis of and treatment of HIV+ KS patients in Zambia and throughout sub-Saharan Africa. This will ultimately inform efforts to better understand KS pathogenesis and develop novel interventional strategies.